US2025312350A1PendingUtilityA1
Inhibitors of rlip76
Est. expiryMay 17, 2042(~15.8 yrs left)· nominal 20-yr term from priority
A61K 45/06A61K 31/4985A61P 35/00C07D 498/04A61K 31/5377
63
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Claims
Abstract
Methods and compositions involving inhibitors of RLIP76 for the treatment or prevention of various types of cancer are disclosed.
Claims
exact text as granted — not AI-modified1 . A method of treating or preventing cancer in a subject, the method comprising: administering to the subject an effective amount of a compound of formula (I):
wherein
X is N or CH;
Y is NH or O when Z is a carbonyl oxygen, or CH when Z is F;
Z is ═O or F;
R 1 is H, OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-Lt) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-Lt) p , a substituted or unsubstituted heterocycloalkoxy, or a substituted or unsubstituted heterocyclosulfide;
Ar 1 is
W is N or C;
R 2 and R 4 are each independently H, halogen, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkyl-L 1 ) p , (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 3 is H, halogen, or C 1-6 lower alkyl;
R 5 is NH 2 , OH or F;
R 6 is H, OH, F, Cl, Br, CH 3 , ethynyl, cyano, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxy, or a substituted or unsubstituted sulfide;
R 7 is nothing when W is N, or H, OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p when W is C;
R 9 and R 10 are each independently H, R 3 , or R 9 and R 10 , and the N atom that connects R 9 and R 10 can form a heterocyclic ring of 4 to 8 members which can further comprise N, O, S, or SO 2 ;
R 11 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
L 1 is independently at each occurrence a bond, O, NH, NR 4 , N(C 1-6 lower acyl), S, SO, SO 2 , CO, CONR 4 , CO 2 , NR 4 CO, OCONH, OCONR 4 , OCO 2 , NR 4 CONR 4 , NR 4 CSNR 4 , NR 4 CO, OCO, SO 2 NR 4 , or NR 4 SO 2 ;
p is 1-3, wherein each repeat unit can be the same or different with respect to both cyclic and linear elements; and
wherein each of R 1 —R 11 , independently, can optionally be substituted with up to 3 substituents selected from the group consisting of OH, CN, C 1-6 lower alkyl, C 1-6 lower alkoxy, C 1-6 lower alkylthio, C 1-6 lower alkylamino, C 1-6 lower dialkylamino, C 1-6 lower acyloxy, optionally substituted phenyl, optionally substituted C 5-6 heteroaryl, halogen, CF 3 , OCF 3 , oxo, (OCH 2 CH 2 O) 1-10 OH, and (OCH 2 CH 2 O) 1-10 OCH 3 ;
or an enantiomer, diastereoisomer, racemic mixture, or salt(s) thereof.
2 . The method of claim 1 , wherein any hydrogen or carbon present in the compound are replaced by a corresponding isotope 2 H, 3 H, 13 C or 14 C.
3 . The method of claim 1 or 2 , wherein the compound of formula (I) inhibits a RAL-interacting protein.
4 . The method of any of claims 1-3 , wherein the RAL-interacting protein is RLIP76.
5 . The method of any of claims 1 - 5 , wherein the compound of formula (I) binds to a transporter substrate binding site of RLIP76.
6 . The method of any of claims 1-5 , wherein administration of the compound of formula (I) overcomes deleterious effects of p53 gene loss.
7 . The method of any of claims 1-6 , wherein the subject has cancer, is suspected of having cancer, or has been previously been diagnosed with cancer.
8 . The method of any of claims 1-7 , wherein the cancer is breast cancer, colon cancer, lung cancer, hepatocellular cancer, pancreatic cancer, prostate cancer, glioblastoma, melanoma, or ovarian cancer.
9 . The method of any of claims 1-8 , wherein the breast cancer is triple-negative breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma of a breast, medullary carcinoma of a breast, mucinous carcinoma of a breast, papillary carcinoma of a breast, cribriform carcinoma of a breast, invasive lobular carcinoma, inflammatory breast cancer, lobular carcinoma in situ, male breast cancer, molecular subtypes of breast cancer, Paget's disease of a nipple, phyllodes tumors of a breast, metastatic breast cancer, or combinations thereof.
10 . The method of any of claims 1-9 , wherein the compound is administered orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intraperitoneally, intrapleurally, intranasally, intraocularly, intrapericardially, intraprostatically, intrarectally, intrathecally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularly, intravitreally, liposomally, locally, mucosally, orally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via localized perfusion, bathing target cells directly, or any combination thereof.
11 . The method of any of claims 1-10 , wherein the administration is done prior to, concurrently with, or subsequent to chemotherapy, surgical treatment, or radiation treatment.
12 . The method of any of claims 1-11 , wherein the compound of formula (I) is administered to the subject at least two, three, four, five, six, seven, eight, nine or ten times.
13 . The method of any of claims 1-12 , wherein the subject is administered at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, or 300 μg/kg or mg/kg.
14 . The method of any of claims 1-13 , wherein said subject is further administered a distinct cancer therapy.
15 . The method of any of claims 1-14 , wherein said distinct cancer therapy comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy.
16 . The method of any of claims 1-15 , wherein the compound of formula (I) is further defined as:
17 . The method of any of claims 1-15 , wherein the compound of formula (I) is at least one of the following compounds:
18 . The method of any of claims 1-17 , wherein the compound is not
19 . The method of any one of claims 1-18 , wherein the compound of formula (I) is administered at a dose, or results in a biological concentration of, between approximately 0.001 μM to 1 mM.
20 . A method for inhibiting a RAL-interacting protein in a cell comprising providing to the cell an effective amount of a RAL-interacting protein inhibitor, wherein the RAL-interacting protein inhibitor is a compound of the formula (I):
wherein
X is N or CH;
Y is NH or O when Z is a carbonyl oxygen, or CH when Z is F;
Z is ═O or F;
R 1 is H, OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p , a substituted or unsubstituted heterocycloalkoxy, or a substituted or unsubstituted heterocyclosulfide;
Ar 1 is
W is N or C;
R 2 and R 4 are each independently H, halogen, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkyl-L 1 ) p , (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 3 is H, C 1-6 lower alkyl;
R 5 is NH 2 , OH or F;
R 6 is H, OH, F, Cl, Br, CH 3 , ethynyl, cyano, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxy, or a substituted or unsubstituted sulfide;
R 7 is nothing when W is N, or H, OH, OR 9 , OCOR 11 , OCOR 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo,
cyano, nitro, C 1-6 lower alkyl, C 2 _lower alkenyl, C 2 _lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p when W is C;
R 9 and R 10 are each independently H, R 3 , or R 9 and R 10 , and the N atom that connects R 9 and R 10 can form a heterocyclic ring of 4 to 8 members which can further comprise N, O, S, or SO 2 ;
R 11 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
L 1 is independently at each occurrence a bond, O, NH, NR 4 , N(C 1-6 lower acyl), S, SO, SO 2 , CO, CONR 4 , CO 2 , NR 4 CO, OCONH, OCO NR 4 , OCO 2 , NR 4 CONR 4 , NR 4 CSNR 4 , NR 4 CO, OCO, SO 2 NR 4 , or NR 4 SO 2 ,
p is 1-3, wherein each repeat unit can be the same or different with respect to both cyclic and linear elements; and
wherein each of R 1 —R 11 , independently, can optionally be substituted with up to 3 substituents selected from the group consisting of OH, CN, C 1-6 lower alkyl, C 1-6 lower alkoxy, C 1-6 lower alkylthio, C 1-6 lower alkylamino, C 1-6 lower dialkylamino, C 1-6 lower acyloxy, optionally substituted phenyl, optionally substituted C 5-6 heteroaryl, halogen, CF 3 , OCF 3 , oxo, (OCH 2 CH 2 O) 1-10 OH, and (OCH 2 CH 2 O) 1-10 OCH 3 ;
or an enantiomer, diastereoisomer, racemic mixture, or salt(s) thereof.
21 . The method of claim 20 , wherein the cell is cancer cell.
22 . The method of claim 20 or 21 , wherein the cell is in a patient.
23 . The method of claim 22 , wherein the patient is a cancer patient.
24 . The method of any of claims 20-23 , wherein the subject has, is suspected of having, or is diagnosed with breast cancer, colon cancer, lung cancer, hepatocellular cancer, pancreatic cancer, prostate cancer, glioblastoma, melanoma, or ovarian cancer.
25 . The method of any of claims 20-24 , wherein the RAL-interacting protein is RLIP76.
26 . The method of any of claims 20-25 , wherein the RAL-interacting protein inhibitor binds to a transporter substrate binding site of RLIP76.
27 . The method of any of claims 20-26 , wherein providing the compound of formula (I) overcomes deleterious effects of p53 gene loss.
28 . The method of any of claims 20-25 x 1 , wherein providing the RAL-interacting protein inhibitor to the cell is performed more than once.
29 . The method of any of claims 1-28 , wherein the compound of formula (I) is provided at a dose between approximately 0.001 μM to 1 mM.
30 . The method of any of claims 1-26 x 1 , wherein any hydrogen or carbon present in the compound are replaced by a corresponding isotope 2 H, 3 H, 13 C or 14 C.
31 . The method of any of claims 20-26 x 2 , wherein the compound of formula (I) is further defined as:
32 . The method of any of claims 20-26 x 1 , wherein the RAL-interacting protein inhibitor is at least one of the following compounds
33 . The method of any of claims 20-32 , wherein the RAL-interacting protein inhibitor is not
34 . A method of treating or preventing cancer in a subject, the method comprising: administering to the subject an effective amount of a compound of formula (II):
wherein
E 1 and E 2 are independently H or F, or one of E and E 2 is H and the other OH, CCH or CN, or E and E 2 may be taken together to be ═O or ═CH 2 ;
Ar 2 is
L 2 is —CH 2 CH 2 —, —CH 2 CHR 2 —, —CH 2 NH—, —NHCH 2 —, —CH 2 NR 3 —, —NHCHR 3 —, —CH 2 O—, —OCH 2 —, —OCHR 3 —, —COCH 2 —, —COCHR 2 —, —CH 2 CO—, —CH 2 S—, —CH 2 SO—, —CH 2 SO(NH)—, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 —, —SO(NH)CH 2 —, —SCHR 3 —, —SOCHR 3 —, —SO 2 CHR 3 —, —SO(NH)CHR 3 —, —CH 2 SO 2 —, —SO 2 CHR 2 —, —SOCHR 2 —, —SONHCHR 2 —, —NHS—, —NHSO—, —NHSO 2 —, —SNH—, —SONH—, —SO 2 NH—, —NHNH—, —SNR 3 —, —SONR 3 —, —SO 2 NR 3 —, —NHR 3 —, —R 3 NH—, —NHO—, —ONH—, CONH—, —NHCO—, —CONH—, —ONR 3 —, —NR 3 CO—, —CONR 3 —, —OCO— or —COO—;
R 1 is OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 1 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p , a substituted or unsubstituted heterocycloalkoxy, or a substituted or unsubstituted heterocyclosulfide;
R 2 is H, OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 3 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p , with the proviso that the L 1 directly bonded to L 2 is only selected from a bond, CO, CONR 4 or CO 2 ;
R 4 is H or C 1-6 lower alkyl;
R 5 is NH 2 , OH, or F;
R 6 is H, F, Cl, Br, CH 3 , ethynyl or cyano;
R 7 is H, OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 8 is CH 2 OH, CH 2 F, CHF 2 , CF 3 , CHO, CO 2 H, CO 2 Me, CONH 2 , or CONHMe;
R 9 and R 10 are each independently H, R 3 , or R 9 and R 10 , and the N atom that connects R 9 and R 10 can form a heterocyclic ring of 4 to 8 members which can further comprise N, O, S, or SO 2 ;
R 11 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
L 1 is independently at each occurrence a bond, O, NH, NR 4 , N(C 1-6 lower acyl), S, SO, SO 2 , CO, CONR 4 , CO 2 , NR 4 CO, OCONH, OCONR 4 , OCO 2 , NR 4 CONR 4 , NR 4 CSNR 4 , NR 4 CO, OCO, SO 2 NR 4 , or NR 4 SO; and
p is 1-3, wherein each repeat unit can be the same or different with respect to both cyclic and linear elements;
wherein each of R 1 —R 11 , independently, can optionally be substituted with up to 3 substituents from the following list, OH, CN, C 1-6 lower alkyl, C 1-6 lower alkoxy, C 1-6 lower alkylthio, C 1-6 lower alkylamino, C 1-6 lower dialkylamino, C 1-6 lower acyloxy, optionally substituted phenyl, optionally substituted C 5-6 heteroaryl, halogen, CF 3 , CF 3 O, oxo, (OCH 2 CH 2 O) 1-10 OH, and (OCH 2 CH 2 O) 1-10 OCH 3 ;
or an enantiomer, diastereoisomer, racemic mixture, or salt(s) thereof.
35 . The method of claim 34 , wherein any hydrogen or carbon present in the compound are replaced by a corresponding isotope 2 H, 3H, 13 C or 14 C.
36 . The method of claim 34 or 35 , wherein the compound inhibits a RAL-interacting protein.
37 . The method of any of claims 34-36 , wherein the RAL-interacting protein is RLIP76.
38 . The method of any of claims 34-37 , wherein the compound binds to a transporter substrate binding site of RLIP76.
39 . The method of any of claims 34-38 , wherein administration of the compound overcomes deleterious effects of p53 gene loss.
40 . The method of any of claims 34-39 , wherein the subject has cancer, is suspected of having cancer, or has been diagnosed with cancer.
41 . The method of any of claims 34-40 , wherein the cancer is breast cancer, colon cancer, lung cancer, hepatocellular cancer, pancreatic cancer, prostate cancer, glioblastoma, melanoma, or ovarian cancer.
42 . The method of any of claims 34-41 , wherein the breast cancer is triple-negative breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma of a breast, medullary carcinoma of a breast, mucinous carcinoma of a breast, papillary carcinoma of a breast, cribriform carcinoma of a breast, invasive lobular carcinoma, inflammatory breast cancer, lobular carcinoma in situ, male breast cancer, molecular subtypes of breast cancer, Paget's disease of a nipple, phyllodes tumors of a breast, metastatic breast cancer, or combinations thereof.
43 . The method of any of claims 34-42 , wherein the composition is administered orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intraperitoneally, intrapleurally, intranasally, intraocularly, intrapericardially, intraprostatically, intrarectally, intrathecally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularly, intravitreally, liposomally, locally, mucosally, orally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via localized perfusion, bathing target cells directly, or any combination thereof.
44 . The method of any of claims 34-43 , wherein the administration is done prior to, concurrently with, or subsequent to chemotherapy, surgical treatment, or radiation treatment.
45 . The method of any of claims 34-44 , wherein the compound is administered to the subject at least two, three, four, five, six, seven, eight, nine or ten times.
46 . The method of any of claims 34-45 , wherein the subject is administered at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, or 300 μg/kg or mg/kg.
47 . The method of any of claims 34-46 , wherein said subject is further administered a distinct cancer therapy.
48 . The method of any of claims 34-47 , wherein said distinct cancer therapy comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy.
49 . The method of any of claims 34-48 , wherein the compound of formula (II) is further defined as:
50 . A method for inhibiting a RAL-interacting protein in a cell comprising providing to the cell an effective amount of a RAL-interacting protein inhibitor, wherein the RAL-interacting protein inhibitor is a compound of the formula (II):
wherein
E 1 and E 2 are independently H or F, or one of E and E 2 is H and the other OH, CCH or CN, or E and E 2 may be taken together to be ═O or ═CH 2 ;
Ar 2 is R 7
L 2 is —CH 2 CH 2 —, —CH 2 CHR 2 —, —CH 2 NH—, —NHCH 2 —, —CH 2 NR 3 —, —NHCHR 3 —, —CH 2 O—, —OCH 2 —, —OCHR 3 —, —COCH 2 —, —COCHR 2 —, —CH 2 CO—, —CH 2 S—, —CH 2 SO—, —CH 2 SO(NH)—, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 —, —SO(NH)CH 2 —, —SCHR 3 —, —SOCHR 3 —, —SO 2 CHR 3 —, —SO(NH)CHR 3 —, —CH 2 SO 2 —, —SO 2 CHR 2 —, —SOCHR 2 —, —SONHCHR 2 —, —NHS—, —NHSO—, —NHSO 2 —, —SNH—, —SONH—, —SO 2 NH—, —NHNH—, —SNR 3 —, —SONR 3 —, —SO 2 NR 3 —, —NHR 3 —, —R 3 NH—, —NHO—, —ONH—, CONH—, —NHCO—, —CONH—, —ONR 3 —, —NR 3 CO—, —CONR 3 —, —OCO— or —COO—;
R 1 is OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 1 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p , a substituted or unsubstituted heterocycloalkoxy, or a substituted or unsubstituted heterocyclosulfide;
R 2 is H, OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 3 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p , with the proviso that the L 1 directly bonded to L 2 is only selected from a bond, CO, CONR 4 or CO 2 ;
R 4 is H or C 1-6 lower alkyl;
R 5 is NH 2 , OH or F;
R 6 is H, F, Cl, Br, CH 3 , ethynyl or cyano;
R 7 is H, OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 8 is CH 2 OH, CH 2 F, CHF 2 , CF 3 , CHO, CO 2 H, CO 2 Me, CONH 2 , or CONHMe;
R 9 and R 10 are each independently H, R 3 , or R 9 and R 10 , and the N atom that connects R 9 and R 10 can form a heterocyclic ring of 4 to 8 members which can further comprise N, O, S, or SO 2 ;
R 11 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
L 1 is independently at each occurrence a bond, O, NH, NR 4 , N(C 1-6 lower acyl), S, SO, SO 2 , CO, CONR 4 , CO 2 , NR 4 CO, OCONH, OCONR 4 , OCO 2 , NR 4 CONR 4 , NR 4 CSNR 4 , NR 4 CO, OCO, SO 2 NR 4 , or NR 4 SO; and
p is 1-3, wherein each repeat unit can be the same or different with respect to both cyclic and linear elements;
wherein each of R 1 —R 11 , independently, can optionally be substituted with up to 3 substituents from the following list, OH, CN, C 1-6 lower alkyl, C 1-6 lower alkoxy, C 1-6 lower alkylthio, C 1-6 lower alkylamino, C 1-6 lower dialkylamino, C 1-6 lower acyloxy, optionally substituted phenyl, optionally substituted C 5-6 heteroaryl, halogen, CF 3 , CF 3 O, oxo, (OCH 2 CH 2 O) 1-10 OH, and (OCH 2 CH 2 O) 1-10 OCH 3 ;
or an enantiomer, diastereoisomer, racemic mixture, or salt(s) thereof.
51 . The method of claim 50 , wherein the cell is cancer cell.
52 . The method of claim 50 or 51 , wherein the cell is in a patient.
53 . The method of claim 52 , wherein the patient is a cancer patient.
54 . The method of any of claims 50-53 , wherein the subject has, is suspected of having, or is diagnosed with breast cancer, colon cancer, lung cancer, hepatocellular cancer, pancreatic cancer, prostate cancer, glioblastoma, melanoma, or ovarian cancer.
55 . The method of any of claims 50-54 , wherein the RAL-interacting protein is RLIP76.
56 . The method of any of claims 50-55 , wherein the RAL-interacting protein inhibitor binds to a transporter substrate binding site of RLIP76.
52 x 1 . The method of any of claims 46 - 52 , wherein providing the compound of formula (I) overcomes deleterious effects of p53 gene loss.
57 . The method of any of claims 50-52 x 1 , wherein providing the RAL-interacting protein inhibitor to the cell is performed more than once.
58 . The method of any of claims 50-57 , wherein the compound of formula (I) is provided at a dose between approximately 0.001 μM to 1 mM.
59 . The method of any of claims 50-53 x 1 , wherein any hydrogen or carbon present in the compound are replaced by a corresponding isotope 2 H, 3 H, 13 C or 14 C.
60 . The method of any of claims 50-53 x 2 , wherein the compound of formula (II) is further defined as:
61 . A compound of formula (I):
wherein
X is N or CH;
Y is NH or O when Z is a carbonyl oxygen, or CH when Z is F;
Z is ═O or; —F;
R 1 is OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p , a substituted or unsubstituted heterocycloalkoxy, or a substituted or unsubstituted heterocyclosulfide,
Ar 1 is
W is N or C;
R 2 and R 4 are each independently H, halogen, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkyl-L 1 ) p , (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 3 is H, halogen, or C 1-6 lower alkyl;
R 5 is NH 2 , OH or F;
R 6 is H, OH, F, Cl, Br, CH 3 , ethynyl, cyano, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxy, or a substituted or unsubstituted sulfide;
R 7 is nothing when W is N, or H, OH, OR 9 , OCOR 11 , OCOR 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo,
cyano, nitro, C 1-6 lower alkyl, C 2 _lower alkenyl, C 2 _lower alkynyl, COR 1 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-4 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p when W is C;
R 9 and R 10 are each independently H, R 3 , or R 9 and R 10 , and the N atom that connects R 9 and R 10 can form a heterocyclic ring of 4 to 8 members which can further comprise N, O, S, or SO 2 ;
R 11 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
L 1 is independently at each occurrence a bond, O, NH, NR 4 , N(C 1-6 lower acyl), S, SO, SO 2 , CO, CONR 4 , CO 2 , NR 4 CO, OCONH, OCONR 4 , OCO 2 , NR 4 CONR 4 , NR 4 CSNR 4 , NR 4 CO, OCO, SO 2 NR 4 , or NR 4 SO 2 ;
p is 1-3, wherein each repeat unit can be the same or different with respect to both cyclic and linear elements; and
wherein each of R 1 —R 11 , independently, can optionally be substituted with up to 3 substituents selected from the group consisting of OH, CN, C 1-6 lower alkyl, C 1-6 lower alkoxy, C 1-6 lower alkylthio, C 1-6 lower alkylamino, C 1-6 lower dialkylamino, C 1-6 lower acyloxy, optionally substituted phenyl, optionally substituted C 5-6 heteroaryl, halogen, CF 3 , OCF 3 , oxo, (OCH 2 CH 2 O) 1-10 OH, and (OCH 2 CH 2 O) 1-10 OCH 3 ;
or an enantiomer, diastereoisomer, racemic mixture, or salt(s) thereof.
62 . The compound of claim 61 , wherein any hydrogen or carbon present in the compound are replaced by a corresponding isotope 2 H, 3 H, 13 C or 14 C.
63 . The compound of claim 61 or 62 , wherein the compound is further defined as:
64 . The compound of any of claims 61 to 63 , wherein the compound is further defined as one of:
65 . A compound of the formula (II):
wherein
E 1 and E 2 are independently H or F, or one of E and E 2 is H and the other OH, CCH or CN, or E and E 2 may be taken together to be ═O or ═CH 2 ;
Ar 2 is
L 2 is —CH 2 CH 2 —, —CH 2 CHR 2 —, —CH 2 NH—, —NHCH 2 —, —CH 2 NR 3 —, —NHCHR 3 —, —CH 2 O—, —OCH 2 —, —OCHR 3 —, —COCH 2 —, —COCHR 2 —, —CH 2 CO—, —CH 2 S—, —CH 2 SO—, —CH 2 SO(NH)—, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 —, —SO(NH)CH 2 —, —SCHR 3 —, —SOCHR 3 —, —SO 2 CHR 3 —, —SO(NH)CHR 3 —, —CH 2 SO 2 —, —SO 2 CHR 2 —, —SOCHR 2 —, —SONHCHR 2 —, —NHS—, —NHSO—, —NHSO 2 —, —SNH—, —SONH—, —SO 2 NH—, —NHNH—, —SNR 3 —, —SONR 3 —, —SO 2 NR 3 —, —NHR 3 —, —R 3 NH—, —NHO—, —ONH—, CONH—, —NHCO—, —CONH—, —ONR 3 —, —NR 3 CO—, —CONR 3 —, —OCO— or —COO—;
R 1 is OH, OR 9 , OCOR 11 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 8-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6 -10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p , a substituted or unsubstituted heterocycloalkoxy, or a substituted or unsubstituted heterocyclosulfide;
R 2 is H, OH, OR 9 , OCOR 1 , OCO 2 R 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 10 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 3 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p , with the proviso that the L 1 directly bonded to L 2 is only selected from a bond, CO, CONR 4 or CO 2 ;
R 4 is H or C 1-6 lower alkyl;
R 5 is NH 2 , OH or F;
R 6 is H, F, Cl, Br, CH 3 , ethynyl or cyano;
R 7 is H, OH, OR 9 , OCOR 11 , OCOR 9 , OCONHR 9 , OCONR 9 R 10 , NH 2 NHR 9 , NR 9 R 10 , NHCOR 11 , NR 9 COR 11 , NHCO 2 R 9 , NR 9 CO 2 R 9 , NHCONHR 9 , NR 9 CONR 9 R 10 , SR 9 , SOR 9 , SO 2 R 9 , NHSO 2 R 9 , NR 0 SO 2 R 9 , halo, cyano, nitro, C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, COR 11 , CO 2 R 9 , CONHR 9 , CONR 9 R 10 , C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
R 8 is CH 2 OH, CH 2 F, CHF 2 , CF 3 , CHO, CO 2 H, CO 2 Me, CONH 2 , or CONHMe;
R 9 and R 10 are each independently H, R 3 , or R 9 and R 10 , and the N atom that connects R 9 and R 10 can form a heterocyclic ring of 4 to 8 members which can further comprise N, O, S, or SO 2 ;
R 11 is C 1-6 lower alkyl, C 2-6 lower alkenyl, C 2-6 lower alkynyl, C 3-6 lower cycloalkyl, C 4-6 lower cycloalkenyl, C 4-7 lower heterocycloalkyl, phenyl, C 5-6 heteroaryl, C 8-11 bicycloheteroaryl, C 5-10 bridged bicycloalkyl, C 6-10 bridged bicycloheteroalkyl, (C 4-7 heterocycloalkyl-C 0-4 alkylene-L 1 ) p , or (C 6-10 bridged bicycloheteroalkyl-C 0-4 alkylene-L 1 ) p ;
L 1 is independently at each occurrence a bond, O, NH, NR 4 , N(C 1-6 lower acyl), S, SO, SO 2 , CO, CONR 4 , CO 2 , NR 4 CO, OCONH, OCONR 4 , OCO 2 , NR 4 CONR 4 , NR 4 CSNR 4 , NR 4 CO, OCO, SO 2 NR 4 , or NR 4 SO; and
p is 1-3, wherein each repeat unit can be the same or different with respect to both cyclic and linear elements;
wherein each of R 1 —R 11 , independently, can optionally be substituted with up to 3 substituents from the following list, OH, CN, C 1-6 lower alkyl, C 1-6 lower alkoxy, C 1-6 lower alkylthio, C 1-6 lower alkylamino, C 1-6 lower dialkylamino, C 1-6 lower acyloxy, optionally substituted phenyl, optionally substituted C 5-6 heteroaryl, halogen, CF 3 , CF 3 O, oxo, (OCH 2 CH 2 O) 1-10 OH, and (OCH 2 CH 2 O) 1-10 OCH 3 ;
or an enantiomer, diastereoisomer, racemic mixture, or salt(s) thereof.
66 . The compound of claim 65 , wherein any hydrogen or carbon present in the compound are is replaced by a corresponding isotope 2 H, 3 H, 13 C or 14 C.
67 . The compound of claim 65 or 66 , wherein the compound of formula (II) is further defined as:Join the waitlist — get patent alerts
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